Comparative evaluation of the histamine 3 receptor (H₃R) radiotracers ¹¹C-MK-8278 and ¹¹C-GSK189254

Objectives The central H₃R is a presynaptic autoreceptor regulating release of histamine, and is implicated in a variety of disorders. ¹¹C-GSK189254 [1] and ¹¹C-MK-8278 [2] are PET radiotracers for H₃R imaging. The aim of this study is to compare the imaging properties of these tracers in baboons.

Methods PET scans were acquired for 2 h on the HR+ scanner in two baboons with arterial sampling and metabolite analysis. Brain regional time-activity curves (TACs) were analyzed with 1-tissue (1T) and 2-tissue (2T) compartmental models to estimate volumes of distribution (V_T). Data from preblocking scans with MK-8278 were analyzed using occupancy plots.

Results Metabolism of ¹¹C-MK-8278 (n = 4) was fast, with ~ 40% of parent remaining at 30 min after tracer injection compared with ~80% for ¹¹C-GSK189254 (n = 4). Plasma free fraction was high for both tracers (0.57 for ¹¹C-MK-8278 and 0.68 for ¹¹C-GSK189254). In the brain, ¹¹C-MK-8278 displayed fast kinetics (regional activity peaked at ~20 min) while that for ¹¹C-GSK189254 was protracted (activity uptake plateaued at the end of the 2 h scan). Regional TACs fitted well with the 1T model. Mean V_T values were 28.8, 26.6, 23.5, 19.0, 18.3, 13.4, 11.2, 9.3, and 8.4 mL/cm3 for ¹¹C-MK-8278 in the nucleus accumbens, globus pallidus, putamen, cingulate cortex, caudate, frontal cortex, occipital cortex, pons, and brainstem, and 79.9, 65.9, 71.7, 60.5, 52.2, 44.1, 37.3, 27.6, and 25.1 mL/cm³ for ¹¹C-GSK189254 in the same regions. Comparison of V_T values suggests higher affinity for ¹¹C-GSK189254 and comparable specific binding fractions. Pre-treatment with MK-8278 (0.5 mg/kg) gave receptor occupancy of 97% as measured by ¹¹C-MK-8278, and 96% as measured by ¹¹C-GSK189254.

Conclusions Both ¹¹C-MK-8278 and ¹¹C-GSK189254 provide good specific binding and can be used for receptor occupancy study of H₃R ligands, while the faster kinetics of ¹¹C-MK-8278 may allow more reliable quantification of H₃R alterations in humans.

Research Support Yale PET Center pilot funding.